Derivative of 4-phenyl-carbethoxypiperidine and salts thereof



United States Patent 3,094,528 DERIVATWE (it l-Pi-iENiZL-CAEEETHGXY- PEERIDIINE AND EALTS THEREEJF Martin A. Davis, Montreal, Quebec, Canada, assigner to American Home Products Corporation, New York,

N.Y., a corporation of Deiaware N0 Drawing. Filed June 26, 1961, st. No. 119,386

4 Claims. (Ci. 26%?243) This invention relates to a new pharmacologicallyactive compound, a derivative of 4-phenyl-4-carbethoxypiperidine, to its acid salts, and to the procedure by which these new compounds may be prepared from available starting materials.

The new derivative of 4-phenyl-4-carbethoxypiperidine, both in base and salt forms, is characterized by antitussive action and by high activity as a local anaesthetic agent. It has a relatively low order of toxicity and appears to have promise as a pharmaceutical. The compound, both in base and salt forms, is characterized by antispasmodic activity of a low order.

It may be administered as an antitussive medication in the form of one of its water-soluble salts in solid dosage forms, such as tablets or capsules containing an excipient such as, for example, lactose, a disintegrating agent such as, for example, starch, and a lubricant such as, for example, magnesium stearate, or in liquid preparations such as syrups, which may advantageously contain expectorant and secretolytic additives, such dosage forms to contain from to 50 mg. of the active compound per dosage unit.

The new chemical compound [2-(4-carbethoxy-4- phenypiperidino) ethoxy] ethyl phenothi azine- 1 O-carb oxylate, in base form, has the following structural formula:

Cl t a C-O. CH2. CH2.0.CH2. CH2.N

found in the appended illustrative examples.

EXAMPLE 1 [2- (4-Carbeth0xy-4-Phenylpiperidin0) Ethoxy Ethyl Ph enothiazine-l O-Carboxy late [2 (4 carhethoxy 4 phenylpiperidino)ethoxy]- ethanol Was prepared by the method of Morren, Belg. Patent No. 552,626 (1957); Ind. Chim. Belg. 22, 795 (1957) from 2-(chloroethoxy)ethanol and 4-carbethoxy- 4-phenylpiperidine.

A solution of this basic alcohol (7.7 g., 0.024 mole) in dry pyridine ml.) was added to a slurry of phenothiazine-lO-carboxylic acid chloride (6.3 g., 0.024 mole) in pyridine (10 ml.). The reaction mixture was stirred at room temperature for one hour and subsequently at 85 C. for forty minutes.

The mixture was then cooled, added to ice-water and the gum which had formed was triturated with small por- Fatentecl June 18, 1963 ice tions of dilute hydrochloric acid in order to remove the pyridine. The gum was then shaken with benzene and aqueous sodium carbonate solution, and the benzene layer was separated, dried and evaporated. The residue was taken up in benzene-hexane mixture and treated with charcoal. Evaporation then left 10.6 g. (81% yield) of solid base, of MP. 7382 C. (decomp). The melting point was gradually raised to -87 C. (decornp) on recrystallization from isopropanol-hexane.

Treatment of an ethereal solution of the base with hydrogen chloride gave the hydrochloride salt of [2-(4- carbethoxy 4 phenylpiperidino) ethoxy] ethyl phenothiazine-IO-carboxylate; needles from acetonitrile, MP. 173- 174 C. (decomp.) with prior softening at 114 C.

Analysis confirmed the empiric formula C H ClN O S. Required: Cl, 6.08; S, 5.50%. Found: Cl, 5.69, 5.76; S, 5.64, 5.56%.

The hydrochloride salt was stirred with a mixture of aqueous sodium hydroxide solution and benzene until dissolution was complete. The benzene layer was separated, washed With water, and dried. Evaporation of the solvent and recrystallization of the product from isopropanol-hexane (charcoal) gave a purified sample of the base [2-(4-carbethoxy 4 phenylpiperidino)ethoxylethyl phenothiazine-10-carboxylate, melting at 88-90 C.

Analysis confirmed the empiric formula C l-1 14 0 3. Required: C, 68.11; H, 6.27; S, 5.87%. Found: C, 68.69; H, 6.05; S, 5.68, 5.83%.

EXAMPLE 2 [2 (4 Carbethoxy 4 Phenylpiperidino)Ethoxy]Ethyl Phenothiazine-JO-Carboxylate Methanesulfonic Acid Salt A solution of the free base described in Example 1 in ether-ethyl acetate was treated with a small molar excess of methanesulfonic acid. The methanesulfonic acid addition salt of [2-(4-carbethoxy-4-phenylpiperidino) ethoxyJ- ethyl phenothiazine-IO-carboxylate thus produced was recrystallized from absolute ethanol. It melted at 159- 162 C.

Analysis confirmed the empiric formula C H N O S Required: N, 4.36; S, 9.96%. Found: N, 4.79, 4.89; S, 9.41, 9.38%.

I claim:

1. A compound selected from the group which consists of [2 (4 carhethoxy 4 phenylpiperidino)ethoxy]ethyl phenothiazine-10-carboxylate, and its hydrochloride and methanesulfouic acid addition salts.

2. [2 (4 carbethoxy 4 phenylpiperidino)ethoxy]- ethyl phenothiazine-l0carboxylate.

3. The hydrochloride salt of [2-(4-carbethoxy-4-phenylpiperidino) ethoxy] ethyl phenothiazine-l O-carboxylate.

4. The methanesulfonic acid addition salt of [2-(4-carbethoxy-4-phenylpiperidino)ethoxy1ethy1 phenothiazine- 10-carboxylate.

References Cited in the file of this patent UNITED STATES PATENTS 2,778,824 Von Seernann Ian. 22, 1957 2,858,316 Morren Oct. 28, 1958 2,951,077 Meyers et al. Aug. 30, 1960 2,989,529 Schuler June 30, 1961 3,024,241 Frearson et a1. Mar. 6, 1962 OTHER REFERENCES Chappel et al.: Canadian J. Biochem. & Physio1., vol. 36, pages 475-481 (1958). 

1. A COMPOUND SELECTED FROM THE GROUP WHICH CONSISTS OF (2- (4 - CARBETHOXY - 4 - PHENYLPIPERIDINO)ETHOXYLETHYL PHENOTHIAZINE-10-CARBOXYLATE, AND ITS HYDROCHLORIDE AND METHANESULFONIC ACID ADDITION SALTS. 